Increased Plasma Levels of lncRNAs LINC01268, GAS5 and MALAT1 Correlate with Negative Prognostic Factors in Myelofibrosis.

Sebastian Fantini,Elisa Bianchi,Cristina Mecucci,Leonardo Potenza,Vittorio Rosti,Mario Luppi,Alexis Grande,Francesca Gesullo,Barbara Mora,Paola Guglielmelli,Enrico Tagliafico,Maria Teresa Voso,Chiara Carretta,Michela Zizza,Francesco Passamonti,Selene Mallia,Tiziana Ottone,Costanza Salvadori,Lara Tavernari,Chiara Maccari,Sandra Parenti,Elena Genovese,Alessandro Rambaldi,Margherita Mirabile,Silvia Salmoiraghi,Filippo Badii,Raffaele Palmieri,Monica Maccaferri,Stefano Sartini,Sebastiano Rontauroli,Rossella Manfredini,Alessandro M Vannucchi

doi:10.3390/cancers13194744

Abstract

Simple SummaryMyelofibrosis (MF) displays the worst prognosis among Philadelphia-negative chronic myeloproliferative neoplasms. There is no curative therapy for MF, except for bone marrow transplantation, which however has a consistent percentage of failure. There is thus an urgent need of novel biomarkers to complement current stratification models and to enable better management of patients. To address this issue, we herein measured the plasma levels of several long noncoding RNAs (lncRNAs). Circulating lncRNAs has been already largely described as potential non-invasive biomarkers in cancers. In our study we unveiled that LINC01268, MALAT1 (both p < 0.0001) and GAS5 (p = 0.0003) plasma levels are significantly higher in MF patients if compared with healthy donors, and their increased plasma levels correlate with several detrimental features in MF. Among them, LINC01268 is an independent variable for both OS (p = 0.0297) and LFS (p = 0.0479), thus representing a putative new biomarker suitable for integrate contemporary prognostic models.Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients (n = 143), compared to healthy controls (n = 65). Among these, high levels of LINC01268, MALAT1 or GAS5 correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of LINC01268 (p = 0.0018), GAS5 (p = 0.0008) or MALAT1 (p = 0.0348) are also associated with a poor overall-survival while high levels of LINC01268 correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of LINC01268 is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients’ cohort, it could be used for further studies to design an updated classification model for MF patients.

Highlights

The Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) are clonal stemcell disorders characterized by an increased proliferation and abnormal differentiation of myeloid cells
primary myelofibrosis (PMF) was diagnosed according to 2016 World Health Organization criteria [1], whereas International Working Group for Myeloproliferative neoplasms Research and Treatment criteria were exploited for the diagnosis of PET-MF and post-PV myelofibrosis (PPV-MF) [2]
Eighty-three MF patients (n = 41 PMF, n = 26 PET-MF, n = 16 PPV-MF) and twenty-six healthy donors (HDs) were analyzed for the expression of a list of 38 Long non-coding RNAs (lncRNAs) (Figure 1 and Table S1) by OpenArray real-time PCR platform

Summary

Introduction

The Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs) are clonal stemcell disorders characterized by an increased proliferation and abnormal differentiation of myeloid cells. They include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), the latter identified as prefibrotic (pre-PMF) and overtly fibrotic (overt-PMF) stages according to the degree of bone marrow fibrosis [1]. “High Molecular Risk (HMR)” mutations (e.g., in ASXL1, IDH1/2, SRSF2 and EZH2 genes) have been associated to a worse prognosis and a more frequent leukemic transformation [4]. The serial acquisition of somatic mutations underlies the clonal evolution in MPNs and we have recently reconstructed by single cell analysis the sequence of mutational events associated to PMF progression [5]. Thrombosis and cardiovascular complications, the main cause of death is due to transformation to acute myeloid leukemia (AML), which occurs in 15–20% of cases and is not responsive to conventional therapeutic treatments [4]

Methods

Results

Conclusion